This invention relates generally to the fields of molecular biology and molecular medicine and more specifically to polypeptides involved in the regulation of neuronal apoptotic cell death.
Apoptosis is the term used to describe a type of cellular death that occurs in many tissues as a normal physiological process. This form of cellular demise involves the activation of a built-in genetic program for cell suicide by which cells essentially autodigest. The remnants of these dead cells are then cleared by neighboring phagocytic cells, without resulting in inflammation or scarring. Apoptosis thus stands in marked contrast to cell death caused, for example, by oxygen-deprivation in the settings of myocardial infarction or stroke, where cells lose their energy supplies, rupture and spill their contents into the extracellular milieu. This type of cell death or necrosis often results in inflammation and undesirable consequences.
Apoptosis is required for normal tissue turnover, for the proper development and maintenance of the immune system, for the development of the nervous system, and for the elimination of virus-infected cells. It is a well-ordered process that is characterized by DNA fragmentation, chromatin condensation, membrane blebbing and cell shrinkage. Cells undergoing apoptosis ultimately disassemble into membrane-enclosed vesicles (apoptotic bodies) that are engulfed by neighboring cells and phagocytes, thus preventing an inflammatory response. In addition, apoptosis can be induced to occur by cellular, hormonal or other stimuli to remove unwanted cells from the body. For example, apoptosis occurs in the female reproductive tissues with each menstrual cycle via loss of hormonal stimulation in the absence of a successful pregnancy.
In contrast to the effect of apoptosis in normal cellular processes, when aberrantly regulated, the death of cells through apoptosis can lead to a variety of disease states and pathological conditions. For example, the death of neurons that occurs in diseases such as Alzheimer's dementia and Parkinson's disease shows many hallmarks of apoptosis. Additionally, cell death caused by viral infection can occur through apoptosis in many cases, including T-cell death induced by the human immunodeficiency virus (HIV). Autoimmune diseases, where immune cells inappropriately attack normal tissues, is due, in part, to a failure of apoptosis to occur. In addition, a lack of apoptosis can also play a role in tumorigenesis.
In the nervous system, apoptosis is normally involved in the loss of redundant neurons during fetal development. However, the dysregulation of apoptosis in the nervous system can result in unintended neuronal cell death and can be involved in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Amyotrophic Lateral Sclerosis (ALS). Alzheimer's disease is the most common form of dementia and the fourth leading cause of deaths in adults after heart disease, cancer and stroke. It is estimated that one in ten Americans over the age of 65, and nearly one half of those over the age of 85, have Alzheimer's disease. Amyloid b-protein (ABP) has been identified as a possible causative agent of this disease. Addition of ABP, or of specific fragments of this polypeptide, to cultured neurons and neuronal cell lines results in cell death. Expression of Bcl-2 in these cultured cells can reduce neuronal cell death induced by ABP indicating that apoptosis can contribute to neuronal cell death in Alzheimer's disease. Currently there are no biological screening procedures or effective treatments that can stop the progression of Alzheimer's disease.
Thus there exists a need to identify polypeptide interactions that regulate apoptosis and identify compounds that bind to these polypeptides or modulate the interaction of these polypeptides. The present invention satisfies this need and provides related advantages as well.